Process for the preparation of 1, 2, 5, 6-tetrahydro-1-phenethyl-2-(p-methoxybenzyl)-3, 4-dimethylpyridine and intermediate



hired bittes PRGCESS FOR THE I lRl JPARA'lI0N F 1,25,6-

TETRO 'l-PHENETHYL 2=ip=METHOXY- BENZYL)'-3,4-DIMETHYLPYRIDINE AND ENTER- MEDIATE p Donald E. Rivard, Haddonfield, NJL, assignor to fiimith Kline & French Laboratories, Philadelphia, Pa, a corporation of Pennsylvania No Drawing.- Filed Feb. 25, 1960, Ser. No. 10,334- 6 Claims. (Cl. 260-297) This invention relates to an advantageous process for atenr 0' the preparation of l,2,5,6-tetrahydro-l-phenethyl-2-(pout on. I

lreviously described methods'of reducing 1,2-dihydro- I pyridines to1,2,5,6 tetrahydropyridines do not include control of the reaction temperature nor regulation of the heat produced by the exothermic reaction [J. Org.

Chem. 2211366 (1957)]. ,These methods when applied dimethylpyridine provide very low yields of thecorresponding 1,2,5,6-tetrahydropyridine. The novel method of this invention in which the temperature is controlled and held at about 0 to 18 C. during the hydrogenation and the amount of palladium catalyst used-is less than about 25% by weight based on the dihydropyridine unexpectedly provides greatly increased yields of the'product. For example byuse of the novelhydrogenation the analgetic: agent, phenethyl-6,7-benzmorphan, the yield of this valuable analgesic isincreased about 3 to 4 times over the'yield obtained by following thepreviously'described methods.

The analgetic agent 2'-hydro'xy-5,9-dimethyl-Z-phenethyl-6,7-benzmorphan is prepared from 1,2,5,'6-tetra-- hydro-l-phenethyl-2-(p-methoxybenzyl) 3,4 dimethylto 1,2-dihydro-1-phenethyl-2-(p methoxybenzyl) 3,4-

proces's of this invention as one step in.- the preparation I 2'-hydroXy-5,9 dimethyl-2- V 3,073,837 Patented Jan. 15, 1963 "ice I .2 pyridine, which is produced by the novel hydrogenation process of this invention, bythe following procedure:

The'cyelization is accomplishedlby heating the 1,2,5,6-

tetrahydrod-phenethyl-2 1 (p. methoXybenzyl) 3,4 dimethylpyridine forprolonged periods in the presence of V a cyclizing agent such as. 48% hydrogen bromide solution, optionally, together with acetic acid. The reaction mixture is treated with chloroform and then made basic with ammonium hydroxide solution. The chloroform layer is separated and the chloroform is evaporated in I vacuo while acetone is-added continuously to separate crystals of the product 2-hydroxy-5,9-dimethyl-2-phenethyl-6,7-benz morphanr According to the process of this invention 1,2-dihydro- 1-phenethyl-2-(p-methoxybenzyl)-3,4-dirnethylpyridine is hydrogenated using. a palladium catalyst, such .as palladium-on-charcoal, palladium-onwcalciurn carbonate, palla: dium oxide, or, preferably, palladium-on-barium sulfate,

in an amountby Weight of less than about 25%, preferably about 10 to 20%, of the dihydropyridine. The

' reaction is carried out at a temperature of about 0 to 18 C., preferably about 5 to 15 C. andat about 1" to .4 atmospheres pressure Alternatively larger amounts of" a palladium catalyst; poisoned by the. addition of a catalyst poisonsuch as an alkali metal iodide, forv example potas V r sium iodide or sodium iodide, can be used, The hydrogenation is carried out in a lower alkyl alcohol-hydro- .chloric acid solvent. The preferred lower alkyl alcohol" 7 solvents are those having 1-6 carbon atoms 'such' as methanol, ethanol or. isopropanol. The hydrochloric, acid is advantageously added as a 1N solution. reduction is preferablyrrun until about -90%, of the theoretical amount of hydrogen has been absorbed.

7 The 1,Ldihydro l-phenethyl-2-(p-methoxybenzylj-ifl .i dimethylpyridine starting material for theprocess of this invention is prepared by condensing 3,4-dimethyl l-phen-jk 1 ethylpyridinium I bromideWith p-methox'ybenzyl magnesiurn chloride. Thereaction. is carried outby heating in a solvent in which the reactants" are at least partiallyf, soluble, preferably ethyl ether. Alternativey, otherreactive esters or halides'can beuse'dto form the pyridinium quaternary salt and other halides can be used to form the benzyl Grignard reagent.

The

amass? Of course, other variations in the structure of the reactants and products can obviously be substituted for those described such as other alkoxy compounds for instance the ethoxy or bntoxy analogues. Such equivalent methods are included in this invention.

The following examples are not limiting but are illustrative of the method in accordance with this invention.

Example 1 A slurry of 584 g. of 3,4-dimethyl-l-phenethylpyridinium bromide, prepared by heating 3,4-lutidine with 2-iodoethylbenzene, in 2 l. of dry ether is stirred while 360 g. of p-methoxybenzyl magnesium chloride in ether solution is added. The mixture is stirred for 30 minutes, then treated 2.5 l. of Water containing 625 g. of ammonium chloride and 250 ml. of concentrated ammonium hydroxide. The organic layer is extracted with hydrochloric acid solution. Neutralization of the acidic solution, extraction with ether and evaporation of the ether leaves 1,2-dihydro-1phenethyl-2-(p-methoxybenzyl)-3,4- dimethylpyridine.

A cold solution of 800 g. of 1,2-dihydro-l-phenethyl-Z- (p-methoxybenzyl)-3,4-dimethylpyridine in 2 l. of ethanol, 159 g. of 5% palladiumon-barium sulfate and 7.04 l. of cold 1 N hydrochloric is hydrogenated at 9-15 C. until 43 l. of hydrogen is absorbed. The reaction mixture is filtered and made basic with ammonium hydroxide. The oil is extracted into ether and-the extracts are dried, concentrated and distilled to give 1,2,5,6- tetrahydro 1 phenethyl 2 p-methoxybenzy1)-3,4-dimethylpyridine, B.P. 179-186 C. at 0.3 mm.

A solution of 454 g. of l,2,5,6-tetrahydro-l-phenethyl- 2-(p-methoxybenzyl)-3,4 dimethylpyridine in 750 ml. of acetic acid and 2.75 l. of 48% hydrobromic acid is refluxed for 20 hours. The mixture is poured onto crushed ice and chloroform. Ammonium hydroxide is added until the solution is basic. The chloroform layer is dried and concentrated in vacuo while acetone is added slowly. The crystals are filtered and dried to give 2-hydroxy-5,9- dimethyl-Z-phenethyl 6,7 benzmorphan, M.P. 180 181' C.

Example 2 A cold solution of 1 kg. of 1,2-dihydro-l-phenethyl-Z- (p-methoxybenzyl)-3,4-dirnethylpyridine, prepared as in Example 1, in 2.5 l. of ethanol is mixed with 245 g. of palladium-on-charcoal catalyst, 25 g. of potassium iodide and 7.5 liters of cold 1 N hydrochloric acid. Hydrogenation of this mixture is carried out at 10-15 C. until 54 liters of hydrogen are absorbed. The reaction mixture is filtered and made basic with ammonium hydroxide.

Extraction with ether, concentration and distillation of the extracts gives 1,2,5,6-tetrahydro-1-phenethyl-2-(pmethoxybenzyl)-3,4-dimethylpyridine. 5 A mixture of 400 g. of the above prepared l,2,5,6- tetrahydropyridine and 2.5 l. of 48% hydrobromic acid is refluxed for 24 hours, then quenched with crushed ice and chloroform. Treating with base and working up as in Example 1 gives 2-hydroxy-5,9-dimethyl-2-phenethyl 6,7-benzmorphan.

W1 is claimed is:

l. The method of preparing 1,2,5,6-tetrahydro-l-phenethyl-2-(p-methoxybenzyl) 3,4 dimethylpyridine which comprises hydrogenating 1,2-dihydro-1phenethyl-2-(pmethoxybenzyl)-3,4-dimethylpyridine using less than about 25% by weight of a palladium catalyst at from about -18 C. and at about 1-4 atmospheres pressure.

2. The method of claim 1 in which the catalyst is palladium-on-harium sulfate.

3. The method of claim 2 in which the reaction temperature is about -15 C.

4. The method of claim 1 in which the palladium catalyst is poisoned with potassium iodide.

5. The method of claim 1 in which the reaction is carried out in 1 N hydrochloric acid containing a substantial amount of a lower alkanol.

6. A chemical compound having the following fundamental formula:

GEE-0011: f

CH: JHa

References Cited in the file of this patent UNITED STATES PATENTS 2,516,628 Haury July 25, 1950 2,704,759 Gluesenkamp et al Mar. 22, 1955 2,959,594 Gordon et a1. Nov. 8, 1960 2,967,182 Pohland Jan. 3, 1961 2,972,617 Cislak Feb. 21, 1961 

1. THE METHOD OF PREPARING 1,2,5,6-TETRAHYDRO-1-PHENETHYL-2-(P-METHOXYBENZYL) -3-4-DIMETHYLPYRIDINE WHICH COMPRISES HYDROGENATING 1,2-DIHYDRO-1-PHENTHYL-2-)PMETHOXYBENZYL)-3,4-DIMETHYPYRIDINE USING LESS THAN ABOUT 25% BY WEIGHT OF A PALLADIUM CATALYST AT FORM ABOUT 0-18* C. AND AT ABOUT 1-4 ATMOSPHERES PRSSURE.
 6. A CHEMICAL COMPOUND HAVING THE FOLLOWING FUNDAMENTAL FORMULA: 